* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
4
[ 5900-58-3 ]
[ 57-13-6 ]
[ 13165-35-0 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 8, p. 1699 - 1702
17.1g of 4-chloro-2-aminobenzoic acid (0.1mol), 100mL of methanol was added to the reaction vessel, stirred to dissolve, cooled to -5 ~ 0 ,Slowly added dropwise 10mL thionyl chloride, dropwise addition, remove the ice bath, slowly warmed to room temperature, stirred 0.5h, the reaction was warmed to reflux, the reaction 4h, steamed added 70mL methanol, the next set of applications, the raffinate Add ice water, add sodium bicarbonate to neutral, filter, the filter cake was dissolved with 100mL dichloromethane, filtered to give unreacted 4-chloro-2-amino benzoic acid 1.8g, can be applied directly to the next ester The methylene chloride layer was dried over 5 g of anhydrous sodium sulfate, filtered and the solvent was distilled off to obtain 15.4 g of methyl 4-chloro-2-aminobenzoate (2) in a yield of 83percent.
82%
at 0 - 5℃; for 24 h; Reflux
A single-mouth bottle was charged with 10 g of 2-amino-4-chlorobenzoic acid, 150 ml of methanol, cooled to 0 to 5 ° C, and 10.4 g of thionyl chloride was added dropwise thereto.After the addition was completed, the temperature was refluxed for 24 hrs. It was cooled to room temperature and concentrated under reduced pressure to remove methanol.Add 100 ml of ethyl acetate, 100 ml of 5percent sodium carbonate solution, stir, let stand, separate the aqueous layer, and wash the organic layer with 100 ml of water.Dry over anhydrous sodium sulfate and concentrate under reduced pressureMethyl 2-amino-4-chlorobenzoate 8.9 g, yield 82percent.
62%
Stage #1: With hydrogenchloride In water for 12 h; Reflux Stage #2: With sodium hydroxide In water
Methyl 2-amino-4-chlorobenzoate; To a mixture of 2-amino-4-chlorobenzoic acid (150 g, 0.88 mol) in MeOH (2.6 L) was added cone. HCl (0.5 L, 16.5 mol) and the reaction mixture was allowed to stir at reflux. After 12 h, the reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue and the solution basified with 10percent aqueous NaOH. The resulting precipitate was filtered to give methyl 2-amino-4-chlorobenzoate (101 g, 62percent).
Reference：
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 17, p. 3248 - 3255
[2] Patent: CN106243046, 2016, A, . Location in patent: Paragraph 0047; 0052; 0053; 0073; 0074
[3] Patent: CN107778229, 2018, A, . Location in patent: Paragraph 0021
[4] Patent: WO2010/65134, 2010, A1, . Location in patent: Page/Page column 60
[5] Journal of the Chemical Society, 1947, p. 808,811
[6] Journal fuer Praktische Chemie (Leipzig), 1929, vol. <2> 120, p. 69
[7] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
[8] Chemistry of Heterocyclic Compounds, 2006, vol. 42, # 1, p. 64 - 69
[9] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 10, p. 5803 - 5814
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[11] Organic and Biomolecular Chemistry, 2015, vol. 13, # 47, p. 11486 - 11491
[12] Patent: CN105503668, 2016, A, . Location in patent: Paragraph 0021; 0023
[13] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1919 - 1925
8
[ 89-77-0 ]
[ 18107-18-1 ]
[ 5900-58-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 0 - 20℃; Inert atmosphere
First, into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methanol/DCM (150/100 mL), 2-amino-4-chlorobenzoic acid (10 g, 58.28 mmol, 1.00 equiv). This was followed by the addition of TMSCHN2 (30.7 mL, 1.05 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×20 mL of n-hexane. This resulted in 10.1 g (93percent) of methyl 2-amino-4-chlorobenzoate as a yellow solid.
Reference：
[1] Patent: US3949081, 1976, A,
[2] Patent: US3989689, 1976, A,
12
[ 186581-53-3 ]
[ 89-77-0 ]
[ 5900-58-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 2, p. 738 - 743
13
[ 6280-88-2 ]
[ 5900-58-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 8, p. 1743 - 1754
[2] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
14
[ 34662-32-3 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
[2] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
15
[ 89-63-4 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
[2] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
16
[ 5900-59-4 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1923, vol. 45, p. 1028
17
[ 89-59-8 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
18
[ 5900-55-0 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
19
[ 95-79-4 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
20
[ 67-56-1 ]
[ 5900-56-1 ]
[ 5900-58-3 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1285,1288
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 5, p. 754 - 765
[2] Journal of Medicinal Chemistry, 1997, vol. 40, # 25, p. 4053 - 4068
[3] Journal of the Chemical Society, 1948, p. 1713
24
[ 5900-58-3 ]
[ 544-92-3 ]
[ 58331-97-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4613 - 4627
25
[ 5900-58-3 ]
[ 37585-16-3 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.16667 h; Stage #2: With water; sodium sulfate In tetrahydrofuran at 0℃;
(2-Amino-4-chlorophenyl)methanol. Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2.x.70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69percent yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.
69%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.16667 h; Stage #2: With water In tetrahydrofuran
(2-Amino-4-chlorophenyl)methanol; Methyl 2-amino-4-chlorobenzoate (1.5 g,8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0° C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0° C. with saturated Na2SO4 (50 mL), extracted with Et2O (2.x.70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69percent yield); 1H NMR (400 MHz, MeOD) δ ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H), 6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO2 157.03.
Reference：
[1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 45, p. 9680 - 9684
27
[ 5900-58-3 ]
[ 85392-01-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2004, vol. 41, # 3, p. 435 - 438
[2] Patent: US7115545, 2006, B1, . Location in patent: Page/Page column 2
[3] Patent: WO2015/138791, 2015, A1, . Location in patent: Page/Page column 128; 129
[4] Patent: CN105503668, 2016, A, . Location in patent: Paragraph 0021; 0023
[5] Patent: CN106243046, 2016, A,
28
[ 5900-58-3 ]
[ 107-06-2 ]
[ 85392-01-4 ]
Reference：
[1] Patent: US6583089, 2003, B1,
29
[ 5900-58-3 ]
[ 199850-56-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
With iodine; silver sulfate In ethanol at 20℃; for 0.75 h;
Methyl 2-amino-4-chloro-5-iodobenzoate; To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite.(R). and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3 x 400 mL), water (3 x 400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99percent).
76%
at 20℃; for 0.75 h;
Methyl 2-amino-4-chloro-5-iodobenzoate To a mixture of I2 (6.8 g, 27.0 mmol) and Ag2SO4 (8.4 g, 27.0 mmol) in EtOH (250 mL), methyl 2-amino-4-chlorobenzoate (5.0 g, 27.0 mmol) was added and the resulting mixture was stirred at RT for 45 min. The solid was filtered off and washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was extracted with dichloromethane and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the desired product (6.4 g, 76percent yield) as a white solid. ESI-MS m/z: 311.9 [M + H]+.
55.6%
With iodine; silver sulfate In ethanol
Intermediate 2 : Methyl 2-amino-4-chloro-5-iodobenzoateTo a solution of methyl 2-amino-4-chlorobenzoate (Aldrich, 1 11 g, 600 mmol) and silver sulfate (187 g, 600 mmol) in ethanol (1000 mL) was added dropwise in 8 hours a solution of iodine (152 g, 600 mmol) in ethanol (2000 mL). The reaction mixture was stirred overnight then filtered through a celite plug. The filtrate was concentrated under reduced pressure and the residue was triturated in n-heptane. The resulting solid was filtered, washed with diisopropyl ether to give the title compound methyl 2-amino-4-chloro-5-iodobenzoate (103.76 g, 334 mmol, 55.6percent yield) as a white powder. LCMS: (M+H)+ = 312 ; Rt = 3.46 min.
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, # 10, p. 993 - 1000
[2] Chemical Communications, 2017, vol. 53, # 62, p. 8735 - 8738
[3] Patent: WO2010/65134, 2010, A1, . Location in patent: Page/Page column 60-61
[4] Patent: WO2015/54572, 2015, A1, . Location in patent: Page/Page column 261; 262
[5] Patent: WO2012/119978, 2012, A1, . Location in patent: Page/Page column 50
[6] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 5, p. 443 - 447
[7] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 15, p. 1723 - 1727
[8] Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 917 - 922
[9] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 266
[10] ChemMedChem, 2017, vol. 12, # 3, p. 197 - 201
With iodine; silver sulfate; In ethanol; at 20℃; for 0.75h;
Methyl 2-amino-4-chloro-5-iodobenzoate; To a mixture of iodine (68 g, 0.27 mol) and silver sulfate (84 g, 0.27 mol) in absolute EtOH (2.5 L) was added methyl 2-amino-4-chlorobenzoate (50 g, 0.27 mol). The reaction mixture was allowed to stir at rt for 45 min. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated. The residue was dissolved in EtOAc (2 L) and washed with saturated aqueous NaHCO3 (3 x 400 mL), water (3 x 400 mL), and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give methyl 2-amino-4-chloro-5-iodobenzoate (85 g, 99%).
76%
With iodine; silver sulfate; at 20℃; for 0.75h;
Methyl 2-amino-4-chloro-5-iodobenzoate To a mixture of I2 (6.8 g, 27.0 mmol) and Ag2SO4 (8.4 g, 27.0 mmol) in EtOH (250 mL), methyl 2-amino-4-chlorobenzoate (5.0 g, 27.0 mmol) was added and the resulting mixture was stirred at RT for 45 min. The solid was filtered off and washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was extracted with dichloromethane and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the desired product (6.4 g, 76% yield) as a white solid. ESI-MS m/z: 311.9 [M + H]+.
55.6%
With iodine; silver sulfate; In ethanol;
Intermediate 2 : Methyl 2-amino-4-chloro-5-iodobenzoateTo a solution of methyl 2-amino-4-chlorobenzoate (Aldrich, 1 11 g, 600 mmol) and silver sulfate (187 g, 600 mmol) in ethanol (1000 mL) was added dropwise in 8 hours a solution of iodine (152 g, 600 mmol) in ethanol (2000 mL). The reaction mixture was stirred overnight then filtered through a celite plug. The filtrate was concentrated under reduced pressure and the residue was triturated in n-heptane. The resulting solid was filtered, washed with diisopropyl ether to give the title compound methyl 2-amino-4-chloro-5-iodobenzoate (103.76 g, 334 mmol, 55.6% yield) as a white powder. LCMS: (M+H)+ = 312 ; Rt = 3.46 min.
With iodine; silver sulfate; In ethanol; at 20℃; for 3.0h;
LODINATION of aniline containing compounds: LODINATION was accomplished using a procedure similar to that set forth in the following reference which is herein incorporated by reference in its entirety for all purposes as if fully set forth herein: J. Med. Chem. 2001,44, 6,917-922. The ANTHRANILIC ester in EtOH was added to a mixture of silver sulfate (1 equivalent) and 12 (1 equivalent). The reaction was typically done after 3 hours at room temperature. The reaction was filtered through Celite and concentrated. The residue was taken up in EtOAc and washed with aqueous saturated NAHC03 (3x), water (3x), brine (1X), dried (MGS04), filtered, and concentrated. The crude product (-5 g) was dissolved in MeOH (60-100 mL), NAOH 6 N (25 mL), and water (250 mL). The reactions were typically done after heating at 70-80 C for 4 hours. The reaction mixture was extracted with EtOAc (2x), neutralized with aqueous HCI, filtered to collect the solids, and the solid products were washed with water. The products were dried in vacuo.
Methyl 2-chlorosulfonyl-4-chlorobenzoate At from 0 to 5 C., a solution of 60.9 g (0.88 mol) of sodium nitrite in 100 ml of water was added dropwise to a solution of 139 g (0.75 mol) of methyl 2-amino-4-chlorobenzoate in 400 ml of concentrated hydrochloric acid and the mixture was stirred at 0 C. for another hour. In a second apparatus, 3 g of copper(II) chloride, 3 g of benzyltriethylammonium chloride, 10 ml of water and 400 ml of 1,2-dichloroethane were combined and 64 g (1 mol) of sulfur dioxide were introduced. The diazonium salt described above was subsequently added at from 10 to 150 C., and the mixture was slowly heated to 50 C. A further 54 g (0.84 mol) of sulfur dioxide were then introduced, and stirring was continued at 500 C. for another 30 minutes. After cooling, 7.4 g (0.1 mol) of chlorine gas were then introduced at room temperature, stirring was continued for 15 minutes and the phases which had formed were then separated. The organic phase was dried and the solvent was removed. This gave 207 g of methyl 2-chlorosulfonyl-4-chlorobenzoate. 1H NMR (CDCl3, delta in ppm): 4.00 (s, 3H); 7.75 (m, 2H); 8.18 (m, 1H)
A suspension of methyl 2- amino-4-chlorobenzoate (8.35 g, 45.0 mmol ) in 20% aqueous HC1 (29 mL) were broken up and the mixture was a uniform suspension of fine (3.11 g, 45.0 mmol) in water (7.5 mL) was added dropwise, maintaining the internal temperature below 5 C . The resulting mixture was then stirred for 2 h at 0 C. A solution of S02 (23.1 g, 360 mmol) in AcOH (36.0 mL) and water (3.75 mL) was then prepared by bubbling the gas though the mixed solvents at 0 C until the mass had increased by the required amount. To this SO2 solution was then added CuCl (1.11 g, 11.25 mmol) followed by the diazonium salt solution portionwise over 30 minutes at 0 C . The resulting mixture was then stirred for 1 h at 0 C and 1 h at room temperature, poured into ice water (150 mL) , and extracted with CH2CI2 (3 x 50 mL) . The combined organics were poured into saturated aqueous NaHCOs (75 mL) , and solid NaHCOa was added carefully until effervescence ceased. The organic phase was then separated, washed with brine (50 mL) , dried over NaaSC , and concentrated to provide the crude sulfonyl chloride as a red-brown oil (3.26 g, 81 massl. product by NMR, 22% yield) . This material was used in the next step without further purification.
In 400 g methanol, by adding 4-chloro-2-aminobenzoic acid 100 g (0.58mol), ice water bath cooling, in the 20 C the following, slowly dropping chlorination sulfoxide 131 g (1.1mol) the rear, after dripping slowly heated up to reflow, reflux reaction 14 hours later, for 30-40 C concentrated under reduced pressure, the concentrated to dry. Ice water bath cooling to 0-5C, product without further processing, concentrated hydrochloric acid is added directly to 300 g, in 0-5 C dropwise 30% sodium nitrite solution 150 g (0.65mol), the continued after dropping 0-5 C reaction 1 hour, add copper chloride 8.5 g (0.05mol), and in 5-10 C lower dropwise saturated sulfur dioxide acetic acid solution of 120 g, the continued after dropping 5-10 C reaction 1 hour, after the reaction, by adding 500 g methylene chloride and 200 g of water, stirring 15 minutes after resting layered, water-soluble liquid sheet to, organic layer then using 200 g water washing once, after washing the organic layer is dried and then adding anhydrous sodium sulfate. After drying the filtered anhydrous sodium sulfate, adding N-methylaniline 64.3 g (0.60mol), adding pyridine under stirring 47.5 g (0.60mol), reaction heating 4 hours, after the completion of reaction, to 20-25C, by adding 400 g 5% dilute hydrochloric acid, stirring 15 minutes after resting layered, water-soluble liquid sheet to, an organic layer after concentrating under reduced pressure to obtain brown solid, used for recrystallization 200 g 95% ethanol, to obtain white powdery solid 129.4 g (compound IV), molar yield 65.7%, liquid phase purity 99.54%, melting point 89.4-92.2 C.
2-(4-benzyloxybenzenesulfonylamino)-4-chloro-benzoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; In dichloromethane; at 20℃;
Methyl 2-amino-4-chlorobenzoate (2.5 g, 13.3 MMOL) is added to a solution of 2.5 g (8.84 MMOL) of the title B compound, 4-benzyloxybenzenesulfonyl chloride in 50 mL of DCM, then 1.4 g (1.43 mL, 17. 68 MMOL) of pyridine is added. The mixture is stirred overnight at RT. The organic solution is then washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to a slightly red solid. The solid is adsorbed on 13 g of silica gel and chromatographed (FLASHELUTE 40M silica gel column) using 1 L of an EtOAc (15%) -hexane (85%) mixture as the eluent, followed by 1 L of DCM to afford 2- (4-BENZYLOXYBENZENE-SULFONYLAMINO)-4-CHLORO-BENZOIC acid methyl ester as a white solid.
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
(2-Amino-4-chlorophenyl)methanol. Methyl 2-amino-4-chlorobenzoate (1.5 g, 8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH (429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0 C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0 C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) delta ppm 4.50 (s, 2H), 6.58 (dd, J=8.06, 2.01 Hz, 1H), 6.70 (d, J=2.01 Hz, 1H), 7.01 (d, J=8.06 Hz, 1H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO 157.03.
69%
(2-Amino-4-chlorophenyl)methanol; Methyl 2-amino-4-chlorobenzoate (1.5 g,8.08 mmol) in THF (15 mL) was dropwise added to the suspension of LAH(429 mg, 11.3 mmol) in THF (10 mL) under N2 at 0 C. over 10 min. The resulting mixture was stirred at room temperature for 2 hrs, then the reaction was quenched at 0 C. with saturated Na2SO4 (50 mL), extracted with Et2O (2×70 mL). The combined organic solutions were washed with brine (30 mL), dried on MgSO4, and concentrated on rotary vacuum to afford the expected product as a white solid (874 mg, 69% yield); 1H NMR (400 MHz, MeOD) delta ppm 4.50 (s, 2 H), 6.58 (dd, J=8.06, 2.01 Hz, 1 H), 6.70 (d, J=2.01 Hz, 1 H), 7.01 (d, J=8.06 Hz, 1 H); Mass spec. 157.06 (MH+), Calc. for C7H8ClNO2 157.03.
With sulfur dioxide; N-benzyl-N,N,N-triethylammonium chloride; chlorine; copper(II) chloride; sodium nitrite; In hydrogenchloride; water;
Methyl 2-chlorosulfonyl-4-chlorobenzoate At from 0 to 5 C., a solution of 60.9 g (0.88 mol) of sodium nitrite in 100 ml of water was added dropwise to a solution of 139 g (0.75 mol) of methyl 2-amino-4-chlorobenzoate in 400 ml of concentrated hydrochloric acid, and stirring at 0 C. was continued for 1 hour. In a second apparatus, 3 g of copper(II) chloride, 3 g of benzyltriethylammonium chloride, 10 ml of water and 400 ml of 1,2-dichloroethane were combined and 64 g (1 mol) of sulfur dioxide were introduced. The diazonium salt was then added at 10 to 15 C. as described above [sic], and the mixture was slowly heated to 50 C. A further 54 g (0.84 mol) of sulfur dioxide were then introduced, and stirring at 50 C. was continued for 30 minutes. After cooling, 7.4 g (0.1 mol) of gaseous chlorine were introduced at room temperature, stirring was continued for 15 minutes and the phases which formed were then separated. The organic phase was dried and the solvent was removed. This gave 207 g of methyl 2-chlorosulfonyl-4-chlorobenzoate. 1-NMR (CDCl3, delta in ppm): 4.00 (s, 3H); 7.75 (m, 2H); 8.18 (m, 1H)
EXAMPLE 62 7-Chloro-2,4-dioxo-3-(2-pyridyl)-1,2,3,4-tetrahydroquinoline To a solution of methyl 2-amino-4-chlorobenzoate (2 g, 10.8 mmol) in 1,2-dichlorethane (60 ml) was added 2-pyridylacetic acid hydrochloride (1.9 g, 10.8 mmol), triethylamine (3.2 ml, 22.7 mmol) and bis (2-oxo-3-oxazolidinyl)phosphinic chloride and the reaction refluxed for 8 h. More 2-pyridylacetic acid (1.9 g, 10.8 mmol) and triethylamine (3.2 ml, 22.7 mmol) were added and refluxing continued for a further 16 h. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and dichloromethane (50 ml). The organic phase was dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica (eluding with 50% ethyl acetate/60-90 petrol) to afford methyl 4-chloro-2-(3-pyridyl)acetamidobenzoate as a green solid (2.5 g), m.p. 85-87 C.
With N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;
84.1
Methyl 2-amino-4-chlorobenzoate (200 mg, 1.1 mmol) and diisopropylethyl amine (1045 μL, 5.9 mmol) were dissolved in a solution of dichloromethane (4 mL) and dimethylformamide (2 mL). Benzothiothiophene-2-carbonyl chloride (1060 mg, 5.4 mmol) was added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum and the residue was re-dissolved in 25 mL of ethyl acetate. The reaction mixture was washed one time each with 10 mL portions of water, 0.1 M NaOH, and saturated aqueous NaCl. The organic layer was dried with MgSO4 and concentrated under vacuum. The crude material was used without further purification. MS (EI) for Ci3H9Cl2NO3S: 330 (M+H).
In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 mumol) was dissolved into a mixture of 655 muL DCE and 120 muL DMA, followed by addition of DIPEA (600 mumol, 15 eq.). Benzo[b]thiophene-3-carboxylic acid (21.4 mg, 120 mumol, 3 eq.) and POCl3 (18.2 mg, 120 mumol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 muL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA , Polymer Labs, 297 mumol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 mumol, 20 eq.). The vial was recapped and EPO <DP n="70"/>shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 muL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 muL of IM aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase Cl 8 preparative HPLC (water/acetonitrile w/ 0.1% formic acid, 30% - 100% eluant gradient) to yield the final product (2.9 mg, 95% purity). MS (EI) for C16H10ClNO3S: 332 (M+H).
Stage #1: 2-amino-4-chloro-benzoic acid methyl ester; 4-(4-methoxyphenyl)thiophene-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; trichlorophosphate In DCE; DMA at 20℃;
Stage #2: In DCE; DMA at 20℃;
3
4-Chloro-2- [({4- [4-(methyloxy)pheny I] -2-thienyl} carbonyl)amino] benzoic acid EPO In a 2 mL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). 4-(4-Methoxyphenyl)thiophene-2-carboxylic acid (13.7 mg, 120 μmol, 3 eq.) and POCl3 (28.1 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA , Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of IM aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase C18 preparative HPLC (water/acetonitrile w/ 0.1% formic acid, 30% - 100% eluant gradient) to yield the final product (4.7 mg, 92% purity). MS (EI) for C19Hi4ClNO4S: 388 (M+H).
Stage #1: 2-amino-4-chloro-benzoic acid methyl ester; 2,5-dimethylfuran-3-carboxylic acid With N-ethyl-N,N-diisopropylamine; trichlorophosphate In DCE; DMA at 20℃;
Stage #2: In DCE; DMA at 20℃;
1
In a 2 niL vial, methyl 2-amino-4-chlorobenzoate (7.4 mg, 40 μmol) was dissolved into a mixture of 655 μL DCE and 120 μL DMA, followed by addition of DIPEA (600 μmol, 15 eq.). 2,5-Dimethylfuran-3~carboxylic acid (16.8 mg, 120 μmol, 3 eq.) and POCl3 (18.2 mg, 120 μmol, 3 eq.) were added. The reaction mixture was capped and stirred at room temperature overnight. Another 700 μL of DCE was added to the reaction mixture along with the following resin bound reagents: a resin bound diethylene triamine (PL-DETA , Polymer Labs, 297 μmol, 7.4 eq.) and a hydroxide ion exchange resin (PL-MP Hydroxide, Polymer Labs, 800 μmol, 20 eq.). The vial was recapped and shaken at room temperature overnight. The resin in the reaction mixture was filtered off, rinsed with 300 μL of MeOH and discarded. The combined filtrates were concentrated down in vacuo. The residue was re-dissolved into 1 mL of DMA and 280 μL of IM aqueous NaOH. The solution was stirred at room temperature overnight. The desired product was isolated directly from this solution via reverse phase Cl 8 preparative HPLC (water/acetonitrile w/ 0.1% formic acid, 30% - 100% eluant gradient) to yield the final product (2.3 mg, 95% purity). MS (EI) for Ci4H12ClNO4: 294 (M+H).
With acetic acid; diethylamine; at 150℃; for 2h;Product distribution / selectivity;
Examples 13 to 21:; The reaction and the post-treatment were carried out in the same manner as in Example 5, for which, however, the type of the anthranilic acid derivative was changed. The results are shown in Table 4.
81%
With formic acid; at 145℃; for 12h;
Methyl 2-amino-4-chlorobenzoate (0.1 g, 0.539 mmol)Dissolved in 3mL of HCONH2,Additional formic acid (2.4 mg, 0.054 mmol)Then slowly heat up to 145 C,TLC detects the reaction,The basic reaction was complete at 12h.Cool to room temperature,Filtered to a grayish solidWash the petroleum ether three times,0.078 g was obtained, and the yield was 81%.
for 10h;Reflux;
General procedure: A mixture of 2-aminobenzoic acid (0.1 mol) and formamide (20 mL)was refluxed for 10 h. After the mixture was cooled to room temperature,water (200 mL) was added and the precipitate was filtered off. Thecrude product was recrystallized from ethanol (100 mL) to the desiredintermediate 1 as a white solid.
With iron(III) chloride; 9-bora-bicyclo[3.3.1]nonane; In 2-methyltetrahydrofuran; at 10℃;Inert atmosphere;
Representative procedure for the synthesis of methyl 2-(4-methoxycyclohexylamino) benzoate (3a): To a stirred solution of 194.6 mg (1.2 mmol) of FeCl3 and 2 mL of anhydrous THF at 0 C under nitrogen atmosphere were added 151.2 mg (1.0 mmol) of methyl 2-aminobenzoate (1) and 141.0 mg (1.1 mmol) of <strong>[13482-23-0]4-methoxycyclohexanone</strong> (2a). 6.0 mL of 0.5 M 9-BBN in THF (3.0 mmol) was then added slowly to maintain internal temperature below 5 C. The reaction mixture was further stirred at 0 C for 2 h. After completion of the reaction (monitored by HPLC), 290 muL (3.0 mmol) of diethanolamine was added to the reaction mixture at 0 C and stirred for 30 min to remove 9-BBN by forming an insoluble solid. After filtering out the precipitate, the crude mixture of 3a was purified by column chromatography over silica gel using pure hexanes to 10% ethyl acetate in hexanes as eluent to give 247 mg of 3a (0.94 mmol) as light yellow oil after drying. The corresponding trans-3a and cis-3a were further purified on silica gel.
With potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 0.166667h; Inert atmosphere;
Typical procedure
To a solution of methyl 2-amino-4-chlorobenzoate (300 mg, 1.6 mmol) and ethyl 2-phenoxyacetate (320 mg, 1.8 mmol) in anhydrous THF (9 mL) was added KHMDS (4.8 mL, 1.0 M in THF, 4.8 mmol) in one portion with vigorous stirring under a nitrogen atmosphere. The reaction mixture was stirred at rt until completion of the reaction (10 min) then MeOH was added. The reaction mixture was concentrated under reduced pressure and the resulting residue was taken up in water and acidified with 1 N HCl until precipitation occurred. The precipitate was filtered, washed with EtOH then dried to give 7-chloro-4-hydroxy-3-phenoxyquinolin-2(1H)-one (Table 2, entry 1) as a pale pink powder (449 mg, 92%). 1H NMR (300 MHz, DMSO-d6) δ 11.74 (s, 1H), 11.37 (s, 1H), 7.88 (s, 1H), 7.49-7.13 (m, 4H), 7.10-6.78 (m, 3H). 13C NMR (75 MHz, DMSO-d6) δ 158.8 (s), 157.4 (s), 152.2 (s), 137.2 (s), 134.4 (s), 129.2 (d), 125.3 (s), 124.8 (d), 121.7 (d), 121.6 (d), 115.2 (d), 114.3 (s and d). MS(EI) m/z 288 (MH+).
4
Methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate To a solution of methyl 2-amino-4-chlorobenzoate (93 mg, 0.50 mmol) in pyridine (1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (109 mg, 0.50 mmol) and the reaction was stirred for 72 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to yield Compound 4 as a white solid (101 mg, 55%). 1H NMR (CHLOROFORM-d) δ: 11.13 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.51-7.55 (m, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.31-7.36 (m, 1H), 7.05 (dd, J=8.5, 2.1 Hz, 1H), 3.92 (s, 3H).
19 Preparation of compound 2a1-6
In a flask, anthranilic ester 19a (Lancaster, 12.0 g, 64.7 mmol) and chloroacetonitrile (6.35 g, 84.0 mmol) are mixed and a HCI solution (4M in dioxane, 43.6 mL) is added under stirring. The mixture is heated at 50°C overnight and is cooled to RT. The solvent is removed in vacuo, the residue is suspended in water and the mixture sonicated. The solid is filtered, washed with water several times and the resulting product is dried under high vacuum to afford 2a1 -6.
Stage #1: 2-amino-4-chloro-benzoic acid methyl ester With sodium hydride In tetrahydrofuran for 0.333333h;
Stage #2: 3-chlorosulfonyl-4-methylbenzoic acid chloride In tetrahydrofuran at 20℃;
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